This invention relates generally to magnetic resonance imagining (MRI) and more particularly to MRI using ligands as contrast agents.
For several years, magnetic resonance imaging (MRI) has been proposed as a valuable aid in diagnosing and locating malignant tumors. It has, for example, been known that certain paramagnetic metal ions localize in malignant tumors and decrease the relaxation time (T.sub.1) of hydrogen ions present in water there. Nevertheless, the use of metal ions as contrast agents has been hampered by their inherent high toxicity.
Recently, it has been found that porphyrin and many of its derivatives also localize in malignant tumors. Unfortunately, free porphyrins do not sufficiently effect the relaxation time of water to be effective MRI contrast agents.
Metalloporphyrins have, to some extent, been used to achieve higher contrast on X-rays of neoplastic tissue. One difficulty observed with the use of metalloporphyrins in this context has been the tendancy of some metalloporphyrins to dissociate and release the highly toxic metal ion. Additionally, it is noted that the characteristics of a suitable X-ray image enhancer and a suitable magnetic resonance image enhancer are quite different.
As stated in Brasch, Radiology, Vol. 147, No. 3 (1983), pages 781-788, incorporated herein by reference the criteria for the "ideal" contrast enhancer are as follows:
1. The effects of the contrast agent on the NMR signal should be dependent on concentration and should be reproducible from one examination to the next.
2. The agent should be chemically versatile so that it can be bound to other compounds as a biologic probe and thereby permit selective tissue targeting.
3. The substance should have relatively strong NMR activity (paramagnetism) so as to significantly alter local magnetic characteristics in low concentrations.
4. The contrast agent should be chemically stable and easily stored, preferably in a form suitable for immediate administration.
5. The substance should be relatively easily manufactured from inexpensive starting materials.
6. The substance should be non-reactive in vivo and should be nontoxic in diagnostic doses. Toxicity includes mutagenicity, teratogenicity, carcinogenicity, and immunogenicity.
7. The ideal NMR agent should be quickly deactivated or excreted (i.e., within hours).
Thus, it is not always possible to accurately predict the behavior of a particular potential contrast enhancer, especially when in vivo use is considered. For example, in vivo, there is typically competition from naturally occuring biological compounds for water. This competition reduces the available protons upon which the metalloporphyrin can act to enhance proton spin relaxation and therefore increase signal intensity.